The goal of this research project is to define the pharmacological treatments and physical conditions which provide a selective anesthesia of nerve fibers. For several years we have each done experimental work on axons. We are impressed with the discovery that impulses may fail to conduct in axons and that the control of such conduction is quite sensitive to fiber activity, anesthetic agents and other pharmaceuticals. The constraints on impulse conduction have been learned from research on biophysics of myelinated and unmyelinated fibers, but very little is known about the differences between large and small fibers and between the various fibers in a nerve or tract. How sensitive are different fibers to anesthetics, to impulse activity and physical environment? We seek to discover these differences and to exploit them to control conduction. The clinical aim is to provide physicians with new capabilities in regional anesthesia. In this project we will work simultaneously at three levels to investigate: 1. the ionic permeability of individual large and small mammalian nerve fibers and to discriminate basic biophysical differences between motor and sensory fibers. 2. the temporal relationships between nerve impulse activity and excitability (threshold) of large and small fibers in the whole nerve. 3. the interactions between activity in large and small fibers locally within the nerve trunk and in an integrated mode at the spinal cord. The actions of nerve blocking agents and other modulating drugs will be focused on at all three levels with the ultimate aim of developing directly applicable procedures for the clinical maintenance, and reversal, of selective pain.